The immune system is vital in protecting an organism, particularly a mammal, from invasion of harmful agents. Without such protection, it is likely that the organism would be unable to survive unless enclosed in a completely sterile environment. However, simply having a functional immune system does not provide absolute protection from all foreign substances. For example, some viral infections (e.g., HIV), although foreign, normally do not elicit an immune response, nor do tumor cells, which are simply the organism's own cells that have lost control over their proliferation.
An immune response involves two primary responses. One such response is the “humoral response.” In this response, mature B lymphocytes leave the bone marrow to circulate in the blood or lymph or to reside in various lymphoid organs. When antigen cross-links membrane-bound antibody molecules on a mature B-cell, some of the bound antigen is internalized by receptor-mediated endocytosis. After processing the antigen, the B-cell presents the resulting antigenic peptides, together with a class II MHC molecule, on its membrane. A TH cell specific for the presented antigen-MHC complex then binds to the complex, allowing for a CD40 ligand (CD40L) located on the surface of the TH cell to associate with a CD40 molecule on the surface of a B-cell (i.e., CD40 ligation). This association contributes to the secretion of a number of cytokines (e.g., IL-2, IL-4, IL-5) by the TH cell. The cytokines then stimulate various stages of B-cell division and differentiation, which leads to the production of a population of both antibody-secreting plasma cells and memory cells.
The other primary immune response is the “cell-mediated response.” In this response, cytokines secreted by TH cells help to activate various T effector cells. For example, after a TC cell binds to processed antigen associated with class I MHC molecules on the membrane of an altered self-cell (i.e., cells displaying foreign antigen complexed to an MHC molecule), IL-2 secreted by TH cells stimulates proliferation and differentiation of the TC cell. This process generates cytotoxic T lymphocytes (CTLs), which not only mediate membrane damage to the altered self-cell leading to cell lysis, but also produce populations of TH and TC cells.
As mentioned above, the interaction of CD40 with its ligand (i.e., CD40L) and the functions carried out by cytokines are involved in directing an immune response. CD40, which belongs to the Tumor Necrosis Factor Receptor (TNF-R) family, is a 45-50 kDa glycoprotein of 277 amino acids, with a 193 amino acid extracellular domain composed of four imperfect repeats of about 40 residues, anchored by a superimposable pattern of six cysteines. CD40 was first identified and functionally characterized on B lymphocytes. However, in recent years it has become apparent that CD40 is more widely expressed, including expression on monocytes, dendritic cells, endothelial cells and epithelial cells. Thus, it is now thought that CD40 plays a more general role in immune regulation. CD40L is a polypeptide of 261 amino acids including a 215 amino acid extracellular domain with five cysteines and is a member of the Tumor Necrosis Factor (TNF) family. CD40L is mainly expressed by activated CD4+ T-cells (i.e., TH cells). Recently, however, CD40L expression on basophils, eosinophils, activated B-cells and blood dendritic cells also has been reported (See, van Kooten et al., Curr. Opin. Immunol. 9: 330-337 (1997)).
Cytokines also play a role in directing an immune response. Most mature CD4+ TH cells express one of two cytokine profiles: TH1 or TH2. TH1 cells express IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, INF-δ, GM-CSF and low levels of TNF-α. The TH1 subset promotes delayed-type hypersensitivity, cell-mediated immunity, and immunoglobulin class switching to IgG2a. The TH2 subset induces humoral immunity by activating B-cells, promoting antibody production, and inducing class switching to IgG1 and IgE.
Since there are many different signals involved in an immune response requiring the interaction of a number of molecules, it is apparent that proper communication between these molecules is necessary for an immune response to occur. A better understanding of this communication will allow for many new prophylactic and therapeutic treatment regimens to be developed for various disease states. For example, it has recently been found that CD40 and various cytokines may play a role in cancer as well as a number of infectious diseases. Indeed, it has been determined that certain cytokines (e.g., IFN-γ, TNF-α, etc.) can up-regulate CD40 expression in some malignant cells that constitutively express CD40. It also has been found that treating certain malignant cells (e.g., melanoma cells) with IFN-γ for 24 hours prior to CD40 stimulation has an additive effect on the release of proinflammatory cytokines by the melanoma cells (see, e.g., Von Leoprechting et al., Cancer Research 59: 1287-1294 (Mar. 15, 1999); and Ziebold et al., Arch. Immunol. Ther. Exp. (Warsz) 48(4): 225-233 (2000)). Additionally, it has been determined that low doses of IL-2 may have a certain level of specific activity in the treatment of cancer, HIV infection and AIDS (see, e.g., U.S. Pat. No. 6,054,788).
While these methods of treatment may provide some relief to cancer, infectious disease and other pathologic states, there is a need for more effective treatments. Indeed, according to the American Cancer Society, the lifetime risk that an individual will develop cancer is 1 in 2 for men and 1 in 3 for women. Moreover, 36.1 million people are currently estimated to be living with HIV/AIDS with an estimated 21.8 million people having died from AIDS since the epidemic began (see, Centers for Disease Control and Prevention, National Center for HIV, STD and TB Prevention). Clearly, a need remains for more effective treatment and preventative measures for these and other pathologic states such that they can be sufficiently treated and controlled.
The present invention provides such a method. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.